AUTHOR INFORMATION

Section 1 of 11

Authored by Gloria J Kuhn, DO, PhD, FACEP, Professor, Vice-Chair of Academic Affairs, Dept of Emergency Medicine, Wayne State University School of Medicine; Professor, Department of Internal Medicine, Section of Emergency Medicine, Michigan State University College of Osteopathic Medicine

Gloria J Kuhn, DO, PhD, FACEP, is a member of the following medical societies: American College of Emergency Physicians, American Osteopathic Association, Council of Emergency Medicine Residency Directors, and Society for Academic Emergency Medicine

Edited by Michael S Beeson, MD, MBA, FACEP, Professor of Emergency Medicine, Northeastern Ohio Universities College of Medicine; Program Director, Emergency Medicine Residency, Summa Health System; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Paul Blackburn, DO, Program Director, Department of Emergency Medicine, Maricopa Medical Center; Assistant Professor, Department of Surgery, University of Arizona; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Robert E O'Connor, MD, MPH, Director of Education and Research, Department of Emergency Medicine, Christiana Care Health System; Professor of Emergency Medicine, Thomas Jefferson University

Author's Email:	Gloria J Kuhn, DO, PhD, FACEP
Editor's Email:	Michael S Beeson, MD, MBA, FACEP

eMedicine Journal, February 7 2007, VOLUME 8, Number 2

INTRODUCTION

Section 2 of 11

Background: Viruses account for the largest proportion of childhood pneumonia; viruses decrease in frequency as the etiology of pneumonia in healthy adults, and once again become frequent causes of death and morbidity in persons older than 60 years.

Viral pneumonia is a subset of the pneumonitides, which were at one time called atypical pneumonias. In the past, all pneumonias were labeled atypical if a bacterial pathogen could not be identified with Gram staining and if the pneumonia did not respond to antibiotics. A number of rapid tests to determine viral etiologies have now been developed. Their use in the emergency department (ED) has allowed bedside diagnosis of the etiology of viral pneumonia. This testing is important for both epidemiologic surveillance and treatment because many viral pneumonias have overlapping clinical presentations with each other and bacterial pneumonia, making diagnosis on purely clinical grounds difficult or impossible.

Viral pneumonia can vary from a mild illness to a life-threatening disease with respiratory failure, severe hypoxemia, and other pulmonary pathology. Severe acute respiratory syndrome (SARS) was a recent example of a viral illness associated with high mortality and morbidity secondary to overwhelming pneumonia and pulmonary complications. The spread of disease was controlled with classic techniques of isolation of sick patients and contacts. Currently, the possibility of a pandemic due to an avian influenza virus labeled A/H5N1 is a grave concern. This virus has been spreading from Southern China to other parts of the world, mainly via poultry-to-human transmission, but sporadic cases of human-to-human transmission have occurred. Illness results in overwhelming pulmonary disease and a high mortality rate.

The viral pneumonias impose a heavy burden on society because of morbidity and occasionally high rates of mortality, depending on the virulence of the organism as well as age and comorbidities of the patients. The cost of treating patients, preventing and controlling outbreaks, and attempting to prevent pandemics is also a burden.

The most common viral agents resulting in pneumonia were influenza A; respiratory syncytial virus (RSV); and parainfluenza 1, 2, and 3. Multiple viral pathogens are often identified. Studies show that patients are frequently infected with both bacterial and viral pathogens making it impossible to rule out bacterial disease even when rapid viral test results are positive. Additionally, no unique identifying clinical characteristics are present that allow the physician to differentiate viral disease from bacterial disease in the ED.

Viruses are divided into categories depending on whether the pneumonia they cause is a primary manifestation or part of a multisystem syndrome of disease. Those that cause pneumonia as a primary manifestation of disease include influenza virus types A and B, RSV, adenovirus, parainfluenza virus, rhinovirus, Hantavirus, and cytomegalovirus (CMV). Those that cause pneumonia as part of a multisystem syndrome include Paramyxovirus species (measles), varicella-zoster virus, Epstein-Barr virus, CMV, and herpes simplex virus.

Viral pathogens can be the etiology of community-acquired pneumonia. Although the most common cause of community-acquired pneumonia remains Streptococcus pneumoniae (a fact that may change with the increasing use of pneumococcal vaccines), in as many as 40-60% of patients with community-acquired pneumonia, the etiologic agent is not identified. Furthermore, convincing associations between the patient's individual symptoms, physical findings, laboratory test results, and specific etiologies are lacking. Therefore, no way of accurately determining the etiology of pneumonia during the initial visit to the ED exists. It is recommended that a chest radiograph be obtained in patients with suspected pneumonia, both to find complications such as pleural effusions and to discourage the use of antibiotics in healthy patients with bronchitis rather than pneumonia.

Pathophysiology:

Epidemiology

Viral pathogens account for 1-23% of community-acquired pneumonias in adults, with influenza virus being the most common agent. Overall, the most common cause of community-acquired pneumonia remains S pneumoniae. Furthermore, convincing associations between individual symptoms, physical findings, and specific etiologies are lacking so that firm diagnosis of the agent, whether bacterial or viral, depends on laboratory testing. Fortunately, bedside testing is now available.

The route of spread of viruses depends on the type of virus involved. Routes include large-droplet spread over short distances ( <1 m), hand contact with contaminated skin and fomites and subsequent inoculation onto the nasal mucosa or conjunctiva (eg, rhinovirus, RSV), and small-particle aerosol spread (eg, influenza, adenovirus). Since influenza is efficiently transmitted via small-particle aerosol droplets, generated by coughing and sneezing, explosive outbreaks occur in closed settings such as nursing homes, especially during the winter months. The impact of influenza is high in elderly persons and greatest on those with chronic illnesses. It has been estimated that at least 63% of the 300,000 influenza-related hospitalizations and 85 % of 36,000 influenza-related deaths occur in patients aged 65 years or older, despite this group accounting for only 10% of the population (Whitney, 2004). Pneumonia is a common complication of influenza.

Influenza viruses have segmented RNA genomes and are classified as type A, B, or C. Influenza type A is usually the most virulent pathogen. The influenza virus has 2 envelop glycoproteins, hemagglutinin (H) and neuraminidase (N), which are important for a number of reasons. The hemagglutinin initiates infectivity by binding to cellular sialic acid residues, while the N protein cleaves newly synthesized virus from sialic acid on cell surfaces, thus allowing spread of the virus to other cells. The influenza virus maintains its infectivity by undergoing antigenic drift (small number of amino acid substitutions) and shift (large number of amino acid substitutions) due to changes in the protein structure of the surface protein, hemagglutinin. Epidemics occur when a viral drift occurs, and pandemics are seen with viral shift (two influenza A viruses exchange H or N genes during infection of the same hosts) because most people have no prior immunity to the virus. These 2 envelop proteins are important targets of neutralizing antibody (Falsey, 2006).

Concern is growing that avian influenza, which is a subtype of influenza A, may result in a worldwide pandemic in the near future. This subtype of influenza causes high mortality as a result of pneumonia and respiratory failure. In 1997, 18 cases of human infection were documented with 6 fatalities. The outbreak was thought to be controlled by depopulating 1.5 million chickens in Hong Kong farms and markets. However, human infections have occurred in 2001, 2002, and 2003 in other parts of Asia, and there are reports of the virus being found in poultry and birds in Europe.

The avian influenza virus A/H5N1 has several ominous characteristics, including increased virulence and human-to-human transmission in several cases, rather than bird-to-human transmission, as is usually necessary. In the 1997 Hong Kong outbreak of 18 patients, 11 were younger than 14 years. Seven of the patients recovered, but 11 patients progressed to pneumonia. Of the 11 patients with pneumonia, 6 died from acute respiratory distress syndrome (ARDS) or multisystem organ failure. Reye syndrome and pulmonary hemorrhage were also complications. Significantly, 8 patients treated with amantadine did not have confirmed benefit from treatment. Worldwide, more than 200 human cases of avian influenza from A/H5N1 or subtypes A/H5, A/H7, and A/H9 have been reported, with greater than 50% mortality in those infected with A/H5N1 (Wong, 2006).

SARS is due to a novel coronavirus (CoV) first identified in 2003. This newly discovered virus is now known to have crossed the species barrier through close contact between humans and infected animals. The natural reservoir of disease has not been proved, but a number of species, including the masked palm civet, have shown infection with a related coronavirus. The virus rapidly adapted to the new host and not only became readily transmissible between humans but also more pathogenic. Contaminated sewage from a housing estate was responsible for the first outbreak of SARS in Hong Kong in 2003, before being spread worldwide by travelers and resulting in sporadic outbreaks. The long incubation period complicated containment of the disease. Control of the spread was finally accomplished in 2005 by using traditional public health measures including finding and isolating case-patients, quarantining contacts, and using enhanced infection control.

The virus is moderately infective, with an attack rate that ranges from 2.4-31 cases per 1,000 exposure hours and is transmitted by aerosolization. Globally, 8422 patients were infected and 916 died, for a case-fatality rate of approximately 15%, but this is higher in elderly persons (can exceed 50% in those >60 y) and in those with comorbid diseases (Varia, 2003). The disease is much milder in patients younger than 12 years (mortality rate was 0% for these patients in the Hong Kong outbreak). Mortality was much higher in patients older than 65 years and can exceed 50% for those 60 years and older.

Avian influenza H5N1 is more fulminant than other recent strains of influenza A or SARS. While it shares similar pathology to SARS, it has a 5-fold mortality compared with SARS, and children do not appear to have milder illness. Both SARS and H5N1 viruses appear to have persistence in postmortem lung tissue, which has implications for infection of contacts (Ng, 2006). Persistence of virus in postmortem tissue of patients with both SARS and avian influenza also indicates a failure of the drugs used to treat the disease (including ribavirin in the case of SARS) and the occasional resistance of H5N1 to oseltamivir.

RSV is important both because of the high attack rate in infants, children, and elderly adults, as well as the morbidity and mortality in these groups. Although RSV does not undergo major periodic antigenic changes as does the influenza virus, immunity is incomplete. Reinfection in children and the young is mild, but rates of severe disease and pneumonia increase with increasing age.

Some viruses are extremely fastidious, while others have the capability of surviving on environmental surfaces for as long as 7 hours, on gloves for 2 hours, and on hands for 30 minutes. Hantavirus transmission is thought to occur primarily through inhalation of infected excreta from diseased rodents, although the virus is also present in rodent saliva; therefore, transmission can occur during bites.

In general, patients with the greatest risk for severe disease from viral pneumonia secondary to any viral pathogen are elderly patients, patients who are immunocompromised, and those with underlying chronic illnesses. Pregnant patients are also at increased risk for morbidity and mortality. Hypoxemia and ARDS can occur in patients who are severely ill. Some patients have residual disability from interstitial fibrosis because of viral pneumonia. Infants hospitalized with lower lung infection due to RSV are much more likely to later develop asthma. Adenovirus, influenza A and B, parainfluenza, and RSV account for 70% of nosocomial pneumonias. These infections are common in patients who are institutionalized.

Pathophysiology and pathogenesis

A full understanding of the pathophysiology and pathogenesis of viral diseases does not presently exist.

The mechanism of damage to tissues depends on the virus involved. In some cases, the immune response may contribute to disease manifestation, in addition to controlling the infection and permitting a return to normal health. Immune responses can be categorized according to patterns of cytokine production. Type 1 cytokines promote cell-mediated immunity, while type 2 cytokines mediate allergic responses. Children infected with RSV who develop acute bronchiolitis, rather than mild upper respiratory infection (URI) symptoms, have impaired type 1 immunity or augmented type 2 immunity (Legg, 2003). In addition to humoral responses, cell-mediated immunity appears to be important for recovery from certain respiratory viral infections. Impaired type 1 response may explain why immunocompromised patients have more severe viral pneumonias.

Respiratory viruses damage the respiratory tract and stimulate the host to release multiple humoral factors, including histamine, leukotriene C4, and virus-specific immunoglobulin E in RSV infection and bradykinin, interleukin 1, interleukin 6, and interleukin 8 in rhinovirus infections. RSV infections can also alter bacterial colonization patterns, increase bacterial adherence to respiratory epithelium, reduce mucociliary clearance, and alter bacterial phagocytosis by host cells.

Infection by influenza virus leads to cell death, especially in the upper airway. When direct viral infection of lung parenchyma occurs, hemorrhage is seen along with a relative lack of inflammatory cells. Mucociliary clearance is impaired, and bacterial adherence to respiratory epithelium occurs. Infection with the virus impairs T cells and neutrophil and macrophage function, which leads to impairment of host defenses and may foster bacterial infection of normally sterile areas, including the lower respiratory tract. This impairment of host defenses may explain why as many as 53% of outpatients with bacterial pneumonia have a concurrent viral infection.

SARS mainly attacks the pulmonary system, although there have been a few reports related to other organ systems. The virus targets pneumocytes causing extensive destruction. In addition, an inflammatory and immune reaction results in diffuse alveolar damage (DAD). Bronchiolitis obliterans organizing pneumonia was described by some authors (Ng, 2006).

Avian influenza causes a similar picture but appears more fulminant and rapid in progression. In SARS, the average duration from symptom onset to death was 19.5 days, while 6 patients died during the fifth week of illness. Pathology found in lung tissue depended on when the patient died, with lung congestion and pleural effusion being more prominent in those dying later (Ng, 2006).

As with SARS, the pathology seen in the lungs of patients with avian influenza A/H5N1 depended on the time of death. Avian influenza resulted in extensive consolidation of the lungs with varying degrees of hemorrhage. Some patients showed bloody effusions and diffuse alveolar damage. It should be emphasized that the type of pulmonary pathology seen in both SARS and avian influenza can be seen in severe pneumonias secondary to other etiologic agents (Levy, 2005).

Elderly persons are at increased risk of infection and complications in viral pneumonia because of comorbidities. Waning cellular, humoral, and innate immune functioning may impair viral clearance, which allows spread of the virus to the lower respiratory tract resulting in increased inflammation. Elderly persons also have decreased respiratory muscle strength and protection of the respiratory tract by mucus levels (Falsey, 2006).

Frequency:

• In the US: Influenza is usually seen in epidemics and pandemics in late winter and early spring. Influenza viruses are the most common causes of viral pneumonia in civilian adults and are responsible for high rates of pneumonia among elderly persons who are at particular risk for severe and fatal disease.

  RSV is the most common etiology of viral pneumonia in infants and children and appears to be associated with the later development of asthma (Singh, 2006). However, RSV has become an increasingly important pathogen in the elderly population and is now the second most commonly identified cause of pneumonia in elderly persons, causing 2-9% of the annual 687,000 hospitalizations and 74,000 deaths from pneumonia in this population (Falsey, 2006). Some studies have suggested that RSV-related disease is as frequent as influenza in elderly persons. Approximately 10% of nursing home patients develop RSV infection annually, while 10% of these patients will develop pneumonia. RSV infection is seasonal, with rates that increase in the fall, peak in winter, and return to baseline in the spring. Peak attack rates for RSV occur in the winter in infants younger than 6 months.

  Parainfluenza most often occurs in the late fall or winter and is the second most common viral illness, after RSV, in infants.

• Internationally: SARS and avian influenza have become major threats to health. In the case of avian influenza, a huge economic burden has been imposed in Asia because of the need to cull infected poultry. Many epidemiologists are predicting a pandemic secondary to avian influenza, and intensive work is being done to create vaccines against both SARS and avian influenza.

Mortality/Morbidity: The burden of viral pneumonia, of any etiology, can be huge.

• Influenza is unique among respiratory viruses because epidemics are regularly associated with excess morbidity and mortality.

• Viral pneumonia can vary from a mild illness to a life-threatening disease with severe hypoxemia.

• Some patients have residual morbidity because of permanent damage to the lungs.

• Patients with the highest risk for severe disease are elderly people, immunocompromised patients, and those with underlying chronic diseases.

• Cognitively impaired elderly patients with influenza viral pneumonia may have unusual presentations including fever and altered mental status without cough (Falsey, 2005).

• Only 30% of elderly patients hospitalized with influenza have radiographic infiltrates, while 30% have findings consistent with congestive heart failure or other diseases (Falsey, 2005).

• Both morbidity and mortality occur in young healthy individuals because of viral pneumonia.

• Avian influenza H5N1 has a fulminate course and high mortality rate (5 times greater than SARS).

• Both SARS and avian influenza persist in tissues for a prolonged period of time.

The US census for 2000-2001 listed pneumonia/influenza as the seventh leading cause of death (down from sixth) despite a 7.2% decrease in the mortality rate for these diseases during this period. Severe influenza seasons can result in more than 40,000 excess deaths and more than 200,000 hospitalizations. Morbidity, especially in elderly persons, is also high. Up to 10-12% of patients older than 65 years required a higher level of assistance for activities of daily living after hospitalization for acute respiratory illnesses. In one nursing home outbreak, residents with acute influenza illness showed significant functional decline (Thompson, 2004).

Patients aged 65 years or older are at particular risk for death from viral pneumonia as well as from influenza not complicated by pneumonia. Deaths in these patients account for 89% of all pneumonia and/or influenza deaths. The question of the effectiveness of widespread vaccination in elderly persons is being questioned. A recent meta-analysis of the efficacy, effectiveness, and safety of the influenza vaccine in patients older than 65 years found that vaccination is of benefit to residents of long-term care facilities but in the community is of modest value (Rivetti, 2006). However, the Centers for Disease Control and Prevention (CDC) still recommend immunization of all elderly patients (CDC, 2006).

The SARS epidemic showed a high morbidity and mortality rate. The mortality rate worldwide was approximately 10.5-15%. From 5 cohorts of patients, the ICU admission rate ranged from 20-38%. Mechanical ventilatory support was required in 59-100% of the patients in the ICU. The mortality rate of patients with SARS who were admitted to the ICU ranged from 5-67%. Mortality rates in patients older than 60 years approached 50%. Healthcare workers were at high risk for contracting the disease and accounted for one fifth of all cases. One year after discharge, those who survived continued to have abnormal chest radiograph findings (27.8%) and pulmonary function (23.7%) (Hui, 2005).

Sex:

• Men who are infected develop viral pneumonia at a slightly higher rate than women. Women were at a higher risk for infection during the SARS epidemic.

• Pregnant women with viral pneumonia have a higher risk for severe disease than other females.

• Smokers have a higher risk for pneumonia and severe disease than nonsmokers.

Age: Elderly persons have a higher risk for severe disease, but viral pneumonia can affect people of any age. Altered mental status and fever may be the only signs of influenza pneumonia in elderly, cognitively impaired patients. Cough, fever, and acute onset had only a 30% positive predictive value in elderly persons compared with a 78% positive predictive value in young adults. Elderly persons are at particular risk of death due to SARS.

CLINICAL

Section 3 of 11

History: Most of the viruses causing viral pneumonia present with an influenzalike syndrome consisting of fever, malaise, headache, cough, and myalgias. This presentation makes determination of the etiology, on a purely clinical basis, difficult. Ascertaining immunization status, travel history, and possible exposure is important. In very elderly persons, the only complaint may be fever and change in mental status. Most patients have cough, but in elderly persons, this may be only scant.

Rapid antigen detection kits can provide results within hours, making them useful in the ED. The sensitivity and specificity of these kits varies between 80% and 95%.

Findings with illnesses caused by influenza virus, RSV, parainfluenza, paramyxovirus measles virus, CMV, varicella-zoster virus, herpes simplex virus, SARS, avian influenza, and Hantavirus are as follows:

• Influenza virus: Clinical illness with influenza begins within 18-72 hours of inoculation. In addition to the classic flulike syndrome, patients may develop tracheobronchitis or viral or bacterial pneumonia. Fewer elderly patients have upper respiratory symptoms, but cough is nearly universal and fever is present in more than 70% of patients. However, pneumonia may only present with fever and change in mental status, especially in those already cognitively impaired.

• RSV: While most patients, including infants, with RSV pneumonia have only upper respiratory symptoms, as many as 25-40% develop bronchiolitis and/or pneumonia. Statistics show that as many as 20-25% of infants with pneumonia who require hospitalization are infected with RSV. Lower respiratory disease in infants is preceded by a prodrome of rhinorrhea and, perhaps, poor appetite. Low-grade fever, cough, and wheezing usually occur. The chest examination reveals tachypnea, rales, and fine wheezes. Disease from RSV in young, healthy adults is usually mild, although one study of community-acquired pneumonia showed RSV to be the third most common pathogen (Dowell, 1996) with S pneumoniae and influenza viruses A and B being more common.

• Parainfluenza virus: When bronchiolitis or pneumonia develops secondary to parainfluenza virus, fever persists, and cough may be somewhat productive. Wheezing, tachypnea, and retractions are seen, and severe cyanosis may be present.

• Measles virus: Patients with pneumonia from the measles virus have a rash, and most have Koplik enanthem (pinpoint grayish spots on a red base on the lateral buccal mucosa opposite the 2nd and 14th molars), which appears prior to the rash and is pathognomonic for rubeola. Rales are frequent, and wheezing may be present. Bacterial superinfection is frequent and most often occurs 5-10 days after onset of the rash. Patients vaccinated before 1968 with inactivated vaccine may present with an atypical rash on the extremities, pneumonia, pleural effusion, and peripheral edema.

• CMV: The two patterns of CMV involvement include (1) a multifocal or miliary pattern characterized by discrete spherical lesions as large as 4 mm in diameter, with alveolar hemorrhage, fibrin deposition, and a moderate neutrophilic response; and (2) a diffuse interstitial pneumonitis with interstitial edema, varying degrees of fibrosis, lymphoid cell infiltration, and alveolar-cell hyperplasia.

• Varicella-zoster virus: Pneumonia secondary to varicella-zoster infection occurs 1-6 days after onset of chickenpox, with cough, dyspnea, tachypnea, fever, and occasionally, chest pain or hemoptysis. It tends to be more severe in adults than in children.

• Herpes simplex virus: Pneumonia may occur as a caudal extension of oral mucocutaneous disease within the tracheobronchial tree, with focal or multifocal necrosis (as in tracheal intubations or burns), or as hematogenous dissemination from oral, genital, or cutaneous sources. This type of pneumonia may involve several organs. Herpes simplex pneumonia must be considered in any immunocompromised patient with focal or diffuse pulmonary infiltrates. The presence of mucocutaneous disease, esophagitis, or tracheitis, especially with endotracheal intubation, increases the likelihood of this pneumonia. Positive findings with viral isolation occur readily, often within 1-2 days, but must be interpreted with caution because of the possibility of oral contamination.

• SARS varies in clinical presentation from asymptomatic infection to severe multilobar pneumonia and death. It tends to have a long incubation period.
  • The most common presenting symptoms of SARS in one study were fever (99% of patients), chills (74%), malaise (63%), and myalgia (50%), which are common to almost all viral illnesses, making it difficult to diagnose the disease without reverse transcriptase–polymerase chain reaction (RT-PCR) testing (Choi, 2003). About 10% of patients will have diarrhea. Of symptomatic patients, approximately 20-25% become critically ill and need to be admitted to the ICU, most commonly with acute respiratory failure that fulfills the criteria for acute lung injury (ALI) and ARDS (Choi, 2003).

  • Chest radiographic findings are not distinctive from other viral pneumonias, and, in the Choi study, 6% of patients had negative findings on chest radiographs but showed infiltrates on chest CT (Choi, 2003). Most patients with SARS develop pneumonia, and the mortality rate is high. Spread is usually by droplet. Diagnosis is by RT-PCR, but a negative result cannot rule out the disease. A positive test result should be confirmed by testing a second sample to rule out false-positive results (CDC, 2005). One prospective study has shown that 1-year survivors continue to have a high rate of abnormal pulmonary function (23.7%) and abnormal chest radiographic findings (27.8%) (Hui and Wong, 2005). It is thought that ongoing active alveolitis, probably as a result of an uncontrolled host immune response triggered by the viral antigen, may lead to pulmonary fibrosis in some patients (Hui and Wong, 2005).

• Hantavirus pulmonary syndrome: Hantavirus pulmonary syndrome begins with a prodromal phase of fever and myalgia lasting 3-6 days. GI symptoms, including nausea, vomiting, and pain, often are present. Cough and upper respiratory symptoms are uncommon, in contrast to many of the other viral prodromes to pneumonia. Onset and rapid progression of cough, shortness of breath, fever, and hypotension herald the cardiopulmonary phase of the disease. These manifestations are caused by pulmonary capillary leakage with the resulting development of adult respiratory distress syndrome. Progressive pulmonary edema and respiratory failure can occur in 80-90% of patients within 2 days of hospitalization.

• Avian influenza has a fulminate course and a high mortality rate. The clinical symptoms of avian influenza depend on the etiologic agent. Those infected with A/H7N7 have conjunctivitis and/or an influenzalike illness. In the 1997 outbreak of A/H5N5, 11 of 18 patients were younger than 14 years. Gastrointestinal symptoms of abdominal pain, diarrhea, and vomiting were prominent. Seven recovered but 11 progressed to pneumonia and 6 died of ARDS or multiorgan failure. Reye syndrome and pulmonary hemorrhage were other complications. In the 2004 outbreak, the young were affected more frequently, diarrhea was again prominent, fever was universally present, and the main presenting syndrome was community-acquired pneumonia. Lymphopenia and thrombocytopenia were common findings in all series of outbreaks and were prognostic indicators of ARDS and death. The case-fatality rate ranged from 64-80%. The incidence of asymptomatic or mild infection is unknown.

Physical: Some patients have few, if any, physical findings other than mild fever, while other patients may have respiratory and/or multiorgan failure. Other findings include the following:

• Fever and/or chills

• Cough (with or without sputum production)

• Tachypnea and/or dyspnea

• Tachycardia or bradycardia

• Wheezing

• Rhonchi

• Rales

• Sternal or intercostal retractions

• Dullness to percussion

• Decreased breath sounds

• Pleurisy

• Friction rub

• Hypoxia

• Acute respiratory distress syndrome

Causes: Causes of viral pneumonia include influenza virus, RSV, parainfluenza virus, adenovirus, paramyxovirus, CMV, varicella-zoster virus, herpes simplex virus, Epstein-Barr virus, Hantavirus, and coronavirus SARS-CoV.

• Influenza virus: Influenza viruses are the most common cause of viral pneumonia in civilian adults. Influenza usually is seen in epidemics and pandemics. Three serotypes of influenza virus exist: A, B, and C. Influenza A is the serotype most frequently responsible for major epidemics and pandemics; it is the most frequent cause of viral pneumonia in adults. Influenza type A can alter surface antigens and infect livestock; perhaps, this characteristic accounts for its ability to create a reservoir for infection and cause epidemics in humans. The virus is spread by means of small-particle aerosol and targets the columnar epithelial cells along the entire respiratory tract. Influenza type B causes illness that usually is seen in relatively closed populations such as boarding schools. Influenza type C is less common and occurs as sporadic cases.

• RSV: RSV is the most important cause of lower respiratory tract infection in infants and young children. Recurrence is common in older children and adults, but recurrent disease is usually milder. The rate during an epidemic approaches 100% in certain settings such as daycare centers.

• Parainfluenza virus: Parainfluenza infection occurs early in life and may cause pneumonia. Infection later in life is usually mild. Four antigenically distinct serotypes of the virus exist; however, types 1, 2, and 3 cause more severe disease than that of type 4. Transmission is caused by direct person-to-person contact or large-droplet spread. The incubation period in adults is 3-6 days; in children, the incubation period has not been determined. Parainfluenza viruses are second in importance to only RSV in causing lower respiratory tract disease in children and pneumonia and bronchiolitis in infants younger than 6 months.

• Adenovirus: Adenovirus transmission occurs by means of direct contact with respiratory secretions, infectious aerosols, or fecal-oral material. Infections may occur from pharyngeal or conjunctival inoculation with contaminated water. Forty-seven serotypes exist. Type 7 viruses can cause bronchiolitis and pneumonia in infants. Types 4 and 7 viruses are responsible for outbreaks of respiratory disease in military recruits. Studies of atypical pneumonia in military personnel have shown that adenovirus is the etiology in as many as 40% of cases. Severe adenovirus pneumonia may occur in infants, immunocompromised patients, and rarely, healthy adults.

• Paramyxovirus: Since the development of a measles vaccine, the incidence of paramyxovirus-induced disease has decreased in the United States. Outbreaks still occur, causing disease in unimmunized children and adults. Immunity to measles (rubeola) is maintained throughout one's lifetime. Atypical measles occurs in individuals who were vaccinated with killed-virus vaccine from 1963-1967. Pneumonia occurs in 5% of measles cases, with death from measles in 1 per 1,000 patients. Most deaths are due to pneumonia.

• CMV: CMV is an extremely important cause of pneumonia in immunocompromised patients, because cellular immunity is of paramount importance in controlling the activity of this agent. Reactivation of latent infection is almost universal in transplant recipients and individuals infected with the human immunodeficiency virus. Additionally, CMV infection is immunosuppressive as well, causing further immunocompromise in these patients. The virus has been found in the cervix and in human milk, semen, and blood products. The prevalence of antibodies to CMV in adults ranges from 40-100%, with higher rates in lower socioeconomic areas. In cancer patients receiving allogenic bone marrow transplants, CMV pneumonia has a prevalence of 15% and a mortality rate of 85%, making it the most common cause of death in this population. Acute graft-versus-host disease is the major risk factor for CMV pneumonia in these patients.

• Varicella-zoster virus is spread by the respiratory route or direct contact with skin lesions. Pneumonia is a significant and life-threatening complication in otherwise healthy adults and immunocompromised hosts. This pneumonia is rare in otherwise healthy children but does occur in immunocompromised children.

• Herpes simplex virus is spread by contact with active lesions or viral shed by asymptomatic excreters. While not a classic respiratory virus, herpes simplex virus can cause pneumonia in compromised hosts, with a mortality rate of 80%. Pneumonia may develop from primary infection or reactivation.

• The Epstein-Barr virus is transmitted through infected saliva. Pneumonia as a complication of mononucleosis is very uncommon. The virus can cause pneumonia in the absence of mononucleosis.

• In May 1993, an outbreak of acute fatal respiratory illness in previously healthy adults in the southwestern United States was caused by a newly recognized Hantavirus, currently termed the Sin Nombre virus. The principal animal reservoir for the virus is the deer mouse. Infection occurs after aerosols of infectious excreta are inhaled. Two other agents, isolated in other parts of North America, can cause the Hantavirus pulmonary syndrome. Most cases of the syndrome have occurred in young–to–middle-aged healthy adults in New Mexico, Arizona, and California. A history of exposure to a rural setting, rodents, or agricultural work may suggest the diagnosis.

• SARS is the latest viral disease to result in pneumonia with a high fatality rate. SARS is a particularly challenging disease because its long incubation period allowed seemingly healthy travelers who were infected with the disease to spread it to 30 countries and regions over a period of 1 year. SARS was only contained after intensive use of traditional quarantine practices.

DIFFERENTIALS

Section 4 of 11

Acute Respiratory Distress Syndrome
Asthma
Bronchitis
Chronic Obstructive Pulmonary Disease and Emphysema
Pneumonia, Bacterial
Pneumonia, Immunocompromised
Pneumonia, Mycoplasma

Other Problems to be Considered:

Bronchiolitis
Acute exacerbation of asthma or bronchitis

WORKUP

Section 5 of 11

Lab Studies:

• Because of the difficulty in distinguishing between the various etiologic agents, both viral and bacterial, causing pneumonia, the workup for symptomatic patients with an infiltrate on chest radiograph should include laboratory studies.

• Viral testing: Rapid antigen detection using RT-PRC can provide results rapidly enough for ED use. Test kits can detect influenza, RSV, rhinoviruses, parainfluenza, and other viruses. Sensitivity for influenza in adults ranges between 50% and 60%, and specificity is greater than 90%. Nasal swabs or washings are easy to obtain. SARS can be diagnosed by RT-PCR or by enzyme-linked immunosorbent assays (ELISAs) specific for SARS. A call to the hospital laboratory is suggested to determine what test is being used and whether a specific viral identification should be requested or whether a general request for viral detection will result in testing for a panel of pathogens. If rapid test results are negative but clinical suspicion is high, cultures can be obtained and the patient treated until results are known. Positive viral identification cannot rule out bacterial co-infection.

• Sputum Gram stains and cultures: Sputum Gram stains are often contaminated with oral pathogens and are difficult to obtain. They are not recommended by the American Thoracic Society or the American College of Emergency Physicians. The Infectious Diseases Society of America recommends obtaining a sputum sample, particularly in hospitalized patients.

• The utility of blood cultures in patients with pneumonia remains controversial. Local hospital protocols should be consulted to determine which patients with pneumonia and who are candidates for hospitalization should have blood cultures drawn prior to administration of medications. Leukopenia occasionally is present. Patients with SARS can have multiple laboratory abnormalities including lymphopenia (73%), thrombocytopenia (50%), hyponatremia (60%), and elevated levels of lactate dehydrogenase (47%) and C-reactive protein (75%). Elevated lactate dehydrogenase level in patients with SARS is a predictor of mortality (Choi, 2003).

• ABGs may be of great value in identifying hypoxemia in severe disease but are unnecessary in mild or moderate disease. Pulse oximetry should be obtained in all patients.

Imaging Studies:

• No firm guidelines exist for when to obtain a chest radiograph in patients to aid in diagnosing lower respiratory tract infection. Chest pain, dyspnea, and productive cough are some of the indications used by clinicians. The Infectious Diseases Society of America recommends chest radiography to confirm infiltrates when pneumonia is suspected for the following reasons: the severity of disease may be revealed, detection of pneumonia may not be possible on purely clinical grounds, and antibiotics are not useful for treatment of bronchitis. It is recommended that a chest radiograph be obtained in patients with suspected pneumonia, both to find complications, such as pleural effusions, and to discourage the use of antibiotics in healthy patients with bronchitis rather than pneumonia.

• Antibiotics are recommended for pneumonia, and a chest radiograph is necessary to make this diagnosis.

• Antibiotics have not been shown to be efficacious in bronchitis.

• The widespread use of antibiotics in inappropriate situations is leading to drug resistance and may explain the increases in death rates since 1979.

• Antibiotics can cause adverse drug reactions; thus, they should be avoided when they are not needed. However, if an infiltrate is seen on a chest radiograph, it may be due to viral or bacterial disease or both. In the ED, differentiating the etiology may be impossible.

• None of the viral etiologies of pneumonia result in pathognomonic findings on chest radiographs, and bacterial pneumonia can not be differentiated from viral pneumonia based on radiographic findings. Of concern was the fact that some patients with SARS had negative findings on chest radiographs but infiltrates were seen on chest CT. Chest radiography may reveal the following findings:

• Patchy interstitial or alveolar infiltrate, which may be bilateral or involve 2 or more lobes

• Peribronchial thickening

• Consolidation

• Pleural effusion

Procedures:

• Patients with respiratory failure require endotracheal intubation and ventilator support.

TREATMENT

Section 6 of 11

Prehospital Care:

• Oxygen should be administered to patients with hypoxemia or shortness of breath.

• Emergency medical personnel should administer oxygen if the patient is dyspneic.

• Some prehospital providers can deliver aerosol treatments with beta-agonists, which may improve the patient's breathing.

• Isotonic sodium chloride solution should be administered to patients who are in shock and have no component of congestive heart failure.

Emergency Department Care: Care in the ED may involve use of the following:

• Oxygen, if the patient is dyspneic

• Beta-agonists, if bronchospasm is present

• Fluids, if dehydration is present

• Acyclovir, if varicella or herpes pneumonia is suspected

• Respiratory isolation

• Antibiotics, if infiltrate is seen on the chest radiograph

• Antibiotics chosen depend on whether the infection is community or hospital acquired

• Mechanical ventilation if respiratory failure is present or impending

MEDICATION

Section 7 of 11

Few specific antiviral agents exist. Acyclovir (for varicella and herpes simplex pneumonia) is efficacious. Ganciclovir and immunoglobulin are used in immunocompromised patients with CMV pneumonia.

Drug Category: Beta-agonists -- Many patients with viral pneumonia have bronchospasm, which is relieved or improved with the use of beta-agonist drugs.

Drug Name	Albuterol (Proventil) -- Beta-agonist for treatment of bronchospasm; relaxes bronchial smooth muscle with its action on beta2-receptors; little effect on cardiac muscle contractility.
Adult Dose	2 puffs qid with metered-dose inhaler; not to exceed 12 inhalations/d; may need to use spacer device to aid inhalation
Pediatric Dose	0.1-0.15 mg/kg PO; not to exceed 2 mg qid
Contraindications	Documented hypersensitivity
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, tricyclic antidepressants, and sympathomimetic agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders

Drug Category: Antivirals -- These agents are used for the treatment of viral infections because they inhibit DNA synthesis and viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase.

Drug Name	Acyclovir (Zovirax) -- Acts by binding viral DNA polymerase (acts as a DNA chain terminator). Virus-infected cells take it up selectively.
Adult Dose	Varicella-zoster infection: 10 mg/kg or 500 mg/m2 q8h IV for 5-7 d Herpes simplex infection: 5 mg/kg q8h IV or 400 mg PO 5 times/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Concomitant use of probenecid or zidovudine prolongs half-life and increases CNS toxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adverse effects include alteration of renal function and CNS side effects; high-dose bolus injection can cause crystallization in renal tubules and subsequent acute tubular necrosis; dehydration, preexisting renal insufficiency, and higher doses are risk factors for renal toxicity and neurotoxicity (eg, altered sensorium, tremor, myoclonus delirium, seizures, extrapyramidal signs in 1-4% of patients); oral acyclovir, even with high doses, has not been associated with renal toxicity; CNS toxicity after IV administration has been reported

Drug Category: Neuraminidase inhibitors -- The surfaces of influenza viruses are dotted with neuraminidase proteins. Neuraminidase is an enzyme that breaks the bonds that hold new virus particles to the outside of an infected cell thus allowing spread of newly synthesized virus to adjacent cells. Neuraminidase inhibitors block the enzyme's activity and prevent new virus particles from being released, thereby limiting the spread of infection. Those available in the United States include zanamivir (Relenza) and oseltamivir (Tamiflu). Patients who present within 48 hours of illness with influenza A and B should be treated with zanamivir or oseltamivir. These agents have also been used to treat pneumonia from SARS and RSV, but they have not been demonstrated to be effective in the complications of viral disease such as pneumonia. Although these agents are approved for use in influenza A infections and were used in patients with SARS, they have not been shown to be effective in preventing serious influenza-related complications such as pneumonia.
Therefore, they are not recommended for use in patients with viral pneumonia due to influenza A but should be administered to high-risk, nonpregnant patients older than 1 year with influenza who present within 48 hours of onset of illness.

Drug Name	Ganciclovir (Cytovene) -- In cells infected with HHV-1 or HHV-2, ganciclovir competitively inhibits incorporation of guanosine triphosphate in viral DNA and terminates chain synthesis. Used for treatment of life-threatening CMV disease. Has been successfully used in immunocompromised patients with CMV retinitis and has been effective in AIDS patients and renal transplant recipients with CMV pneumonia. Has not worked well in marrow transplant recipients with CMV pneumonia unless combined with IV immunoglobulin.
Adult Dose	2.5 mg/kg IV q8h; CMV retinitis dose is 5 mg/kg IV q12h
Pediatric Dose	<3 months: Not established >3 months: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Concomitant administration with cytotoxic drugs (eg, dapsone, vinblastine, Adriamycin, pentamidine, flucytosine, vincristine, amphotericin B, trimethoprim-sulfamethoxazole combinations, other nucleoside analogs) may have additive toxicity in the bone marrow, spermatogonia, and germinal layers of skin and GI mucosa; may cause generalized seizures with concurrent administration of imipenem-cilastatin; serum creatinine level may increase after concurrent use with cyclosporine or amphotericin B; probenecid reduces renal clearance; when didanosine is administered 2 h prior or simultaneously, its bioavailability may increase; conversely, steady-state bioavailability may decrease when didanosine is administered 2 h prior but not when the 2 drugs are administered simultaneously; bioavailability may decrease with zidovudine; increases bioavailability of zidovudine; both drugs can cause granulocytopenia and anemia, combination therapy at full dosing may not be possible
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Clinical toxicity includes granulocytopenia, anemia, and thrombocytopenia; PO route associated with higher rate of CMV retinitis progression compared with IV route; use only when benefits outweigh risks (eg, in advanced HIV disease); half-life and plasma and/or serum concentrations may increase because of reduced renal clearance; doses > 6 mg/kg IV may increase toxicity; rapid infusions may increase toxicity; initially, reconstituted solutions of IV ganciclovir have a high pH (pH =11); phlebitis or pain may occur at site of IV infusion despite further dilution of IV fluids; administration should be accompanied with adequate hydration; photosensitization (photoallergy or phototoxicity) may occur

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Immunocompromised or severely ill patients should be hospitalized.

• Respiratory failure should be considered in any severely ill patient.

• Obtain samples for laboratory testing to aid in diagnosis and therapy for both outpatients and hospitalized patients. Testing can aid in giving prophylaxis to contacts of sick patients sent home and for isolation of hospitalized patients to prevent nosocomial spread of disease.

Further Outpatient Care:

• Patients well enough for discharge should undergo follow-up with their physician in 1-2 days.

• Chest radiographs may not show complete resolution for 1-2 weeks.

In/Out Patient Meds:

• Beta-agonists

• Nonaspirin antipyretics

Deterrence/Prevention:

• Vaccination is not as effective in elderly people as in young healthy people perhaps due to decreased immune response in older patients. The effectiveness/efficacy of widespread vaccination of elderly persons has been called into question. Only elderly patients residing in assisted living conditions showed a clear benefit from vaccination (Rivetti, 2006). Still, influenza A and B vaccination are recommended by the CDC for the following populations (CDC, 2006):

• Children aged 6-23 months

• Children with chronic illnesses

• Adults aged 50 years and older

• People 2 years old or older who have an underlying, long-term illness (heart or lung disease, metabolic disease [such as diabetes], kidney disease, a blood disorder, or a weakened immune system [including people with HIV/AIDS])

• Women who will be pregnant this season

• People who live in nursing homes or other long-term care facilities

• Persons aged 6 months to 18 years and take aspirin daily (to prevent Reye syndrome as a complication of influenza)

• Healthcare workers

• People who have or take care of an infant younger than 6 months (Do not give a flu shot to infants younger than 6 months.)

• Measles vaccine

• Varicella vaccine

Complications:

• Respiratory failure

• Pulmonary fibrosis

• Superimposed bacterial infection

• Adult respiratory distress syndrome

• Reye syndrome

Prognosis:

• The prognosis is good in the vast majority of patients, but it is guarded in elderly or immunocompromised patients. Patients with SARS and avian influenza have a high mortality rate, and about 25% of patients with SARS have residual pulmonary pathology (Hui, 2006).

• Some healthy patients may have severe disease with increased morbidity and mortality.

• Chronic asthma is more common in children with severe lower lung infection due to RSV than in the general population.

Patient Education:

• For excellent patient education resources, visit eMedicine’s Pneumonia Center and Cold and Flu Center. Also, see eMedicine’s patient education articles Viral Pneumonia and Flu in Adults.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Distinguishing viral pneumonia (for which no specific treatment, other than ganciclovir and acyclovir, exists) from bacterial pneumonias (for which antibiotics should be used) is impossible, and patients may have coexisting viral and bacterial pneumonias. Therefore, patients with evidence of acute pneumonia should be treated with antibiotics. Patients coming from home should receive antibiotics recommended for community-acquired pneumonia, and patients who are institutionalized should receive antibiotics recommended for nosocomial infections.

• Failure to administer antibiotics in a timely fashion may result in increased morbidity and mortality. All admitted patients should receive antibiotics in the ED after appropriate laboratory tests have been performed.

• Not all patients with pneumonia have auscultatory changes. Pneumonia is a common cause for change in mental status or decrease in functional status in elderly patients.

• Pulse oximetric findings should be checked and documented in patients who are being discharged.

• Patients who do not improve with outpatient therapy are candidates for admission.

Special Concerns:

• Pregnant patients often have more severe disease.

• Any adult with varicella pneumonia is at risk for severe disease and respiratory failure.

• Elderly persons are more at risk for severe disease.

• Immunocompromised patients have more severe disease.

• Patients with other cardiovascular and pulmonary diseases have more severe disease.

• Consider respiratory isolation for patients with pneumonia during influenza epidemics or those suspected of having SARS based on travel history.

• Smokers are more at risk for severe illness and complications.

TEST QUESTIONS

Section 10 of 11

CME Question 1: The parents of a 6-month-old male infant bring him to the ED because of difficulty breathing. His temperature is 102°F, heart rate is 130, and respiratory rate is 36. His medical history reveals negative findings, and the family history includes diabetes. Sternal and intercostal retractions with alar flaring are observed. Wheezing is present bilaterally. Chest radiograph results are negative. What is the most likely diagnosis?

A: New-onset asthma
B: Early pneumonia
C: Bronchitis
D: Bronchiolitis
E: Aspiration of a foreign body

The correct answer is D: Asthma is unusual with fever, and no family history of it exists. Early pneumonia should be visible on radiographs, and bronchitis is unusual in this age group, unlike bronchiolitis. A foreign body should not cause fever early.

CME Question 2: Which of the following statements regarding severe acute respiratory syndrome (SARS) is correct?

A: SARS has a short incubation period making spread of the disease rare.
B: The viral agent is very fastidious so patients are not contagious.
C: Disease is usually mild with low mortality and morbidity.
D: The disease is best treated with neuraminidase inhibitors.
E: The SARS epidemic was finally contained by traditional quarantine measures.

The correct answer is E: SARS has a long incubation period that aids in spread of disease, and patients are highly contagious. During the SARS epidemic, the mortality rate was around 10%, and many patients required care in the ICU and assisted ventilation. Treatment is supportive with no specific therapy being available.

Pearl Question 1 (T/F): Aspirin should not be prescribed for children with influenza A or varicella infection because of its possible association with Reye syndrome.

The correct answer is True: Because of the possible association with Reye Syndrome, nonaspirin antipyretics (such as acetaminophen) should be used.

Pearl Question 2 (T/F): Young nonsmokers and males are at risk for severe disease due to viral pneumonia.

The correct answer is False: Elderly persons, smokers, pregnant women, and military recruits are at risk for severe disease from viral pneumonia.

Pearl Question 3 (T/F): The route of spread of viruses is dependent on the type of virus involved.

The correct answer is True: The routes of spread include a large-droplet spread over short distances ( <1 m), hand contact with contaminated skin and fomites and subsequent inoculation onto the nasal mucosa or conjunctiva (eg, rhinovirus and RSV), and spread of small-particle aerosols (eg, influenza and adenovirus).

Pearl Question 4 (T/F): Renal failure is the most common cause of death in patients with measles.

The correct answer is False: Pneumonia is the most common cause of death in patients with measles.

BIBLIOGRAPHY

Section 11 of 11

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